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BACKGROUND & AIMS: New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression. METHODS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. RESULTS: Our HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line. CONCLUSIONS: Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection. IMPACT AND IMPLICATIONS: Owing to the limitations of current antiviral therapies for hepatitis B, there is an urgent need for new treatments that target multiple aspects of the HBV replication cycle to improve rates of functional cure. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression, paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.
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The successful use of lipid nanoparticles (LNPs) for clinical development of the COVID-19 mRNA vaccines marked a breakthrough in mRNA-LNP therapeutics. As one of the vital components of LNPs, poly(ethylene glycol)-lipid conjugates (PEG-lipids) influence particle biophysical properties and stability, as well as interactions within biological environments. Reports suggesting that anti-PEG antibodies can be detected quite commonly within the human population raise concerns that PEG content in commercial LNP products could further stimulate immune responses to PEG. The presence of anti-PEG antibodies has been linked to accelerated clearance of LNPs, potentially a source of variability in the biological response to mRNA-LNP products. This motivated us to explore potential PEG alternatives. Herein, we report physicochemical and biological properties of mRNA-LNPs assembled using poly(2-oxazoline) (POx)- and poly(2-oxazine) (POz)-based polymer-lipid conjugates. Notably, we investigated monoacyl lipids as alternatives to diacyl lipids. mRNA-LNPs produced using monoacyl POx/POz-lipids displayed comparable biophysical characteristics and cytocompatibility. Delivery of reporter mRNA resulted in similar transfection efficiencies, in both adherent and suspension cells, and in mice, compared to PEG-lipid equivalents. Our results suggest that monoacyl POx/POz-lipid-containing LNPs are promising candidates for the development of PEG-free LNP-based therapeutic products.
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Lipídeos , Nanopartículas , Oxazóis , Polietilenoglicóis , RNA Mensageiro , Polietilenoglicóis/química , Animais , Nanopartículas/química , Camundongos , RNA Mensageiro/genética , Humanos , Oxazóis/química , Lipídeos/química , Oxazinas/química , LipossomosRESUMO
OBJECTIVE: The aim of this study was to examine perceptions including knowledge, attitudes, and beliefs about e-cigarettes among ethno-culturally diverse Latino adults living in the US, a rapidly growing minority group for which we know little about their e-cigarette perceptions. DESIGN: A total of 25 focus groups with Latinos (n = 180; ages 18-64 years) were conducted in 2014. E-cigarettes users and non-users were recruited via purposive sampling techniques. Participants completed brief questionnaires on sociodemographic factors and tobacco use. Focus group discussions were conducted in English and Spanish, audio-recorded, and transcribed. Data were analyzed using thematic analysis procedures. RESULTS: Participants were of diverse Latino backgrounds. Over one-third (35%) reported current cigarette smoking and 8% reported current e-cigarette or hookah use. Nonsmokers reported experimenting with e-cigarettes and hookah during social occasions. Participants' perceptions towards e-cigarettes were generally formed in comparison to conventional cigarettes. Perceived benefits of using e-cigarettes included their utility as a smoking cessation aid, higher social acceptability, and lower harm compared to conventional cigarettes. Negative perceptions of e-cigarettes included lower overall satisfaction compared to conventional cigarettes and high content of toxins. Socio-cultural factors (e.g. gender roles, familismo, and simpatía) also influenced perceptions of e-cigarette of study participants. CONCLUSIONS: Overall, Latino adults knew relatively little about the potential health risks associated with e-cigarette use. The limited knowledge about and misinformation of e-cigarettes among this rapidly growing minority group have important public health implications. Findings may inform culturally tailored health communication campaigns, which are much needed among underserved US Latino populations in light of low effectiveness of tobacco control and regulatory efforts.
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Sistemas Eletrônicos de Liberação de Nicotina , Abandono do Hábito de Fumar , Vaping , Adolescente , Adulto , Conhecimentos, Atitudes e Prática em Saúde , Hispânico ou Latino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUNDS: Cigarette smoking is strongly associated with major depressive disorder (MDD). However, any genetic etiology of such comorbidity and causal relations is poorly understood, especially at the genome-wide level. METHODS: In the present in silico research, we analyzed summary data from the genome-wide association study of the Psychiatric Genetic Consortium for MDD (n = 191 005) and UK Biobank for smoking (n = 337 030) by using various biostatistical methods including Bayesian colocalization analysis, LD score regression, variant effect size correlation analysis, and Mendelian randomization (MR). RESULTS: By adopting a gene prioritization approach, we identified 43 genes shared by MDD and smoking, which were significantly enriched in membrane potential, gamma-aminobutyric acid receptor activity, and retrograde endocannabinoid signaling pathways, indicating that the comorbid mechanisms are involved in the neurotransmitter system. According to linkage disequilibrium score regression, we found a strong positive correlation between MDD and current smoking (rg = 0.365; p = 7.23 × 10-25) and a negative correlation between MDD and former smoking (rg = -0.298; p = 1.59 × 10-24). MR analysis suggested that genetic liability for depression increased smoking. CONCLUSIONS: These findings inform the concomitant conditions of MDD and smoking and support the use of self-medication with smoking to counteract depression.
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Causalidade , Transtorno Depressivo Maior/epidemiologia , Estudo de Associação Genômica Ampla , Fumar Tabaco/epidemiologia , Comorbidade , Simulação por Computador , Humanos , Desequilíbrio de Ligação , Análise da Randomização MendelianaRESUMO
Nicotine dependence (ND) is a chronic brain disorder that causes heavy social and economic burdens. Although many susceptibility genetic loci have been reported, they can explain only approximately 5%-10% of the genetic variance for the disease. To further explore the genetic etiology of ND, we genotyped 242 764 SNPs using an exome chip from both European-American (N = 1572) and African-American (N = 3371) samples. Gene-based association analysis revealed 29 genes associated significantly with ND. Of the genes in the AA sample, six (i.e., PKD1L2, LAMA5, MUC16, MROH5, ATP8B1, and FREM1) were replicated in the EA sample with p values ranging from 0.0031 to 0.0346. Subsequently, gene enrichment analysis revealed that cell adhesion-related pathways were significantly associated with ND in both the AA and EA samples. Considering that LAMA5 is the most significant gene in cell adhesion-related pathways, we did in vitro functional analysis of this gene, which showed that nicotine significantly suppressed its mRNA expression in HEK293T cells (p < 0.001). Further, our cell migration experiment showed that the migration rate was significantly different in wild-type and LAMA5-knockout (LAMA5-KO)-HEK293T cells. Importantly, nicotine-induced cell migration was abolished in LAMA5-KO cells. Taken together, these findings indicate that LAMA5, as well as cell adhesion-related pathways, play an important role in the etiology of smoking addiction, which warrants further investigation.
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Adesão Celular/genética , Laminina/genética , Tabagismo/genética , Tabagismo/patologia , Adulto , Negro ou Afro-Americano/genética , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , Tabagismo/etnologia , Estados Unidos , População Branca/genéticaRESUMO
BACKGROUNDS: Although studies have demonstrated that the NCAM1-TTC12-ANKK1-DRD2 gene cluster plays essential roles in addictions in subjects of European and African origin, study of Chinese Han subjects is limited. Further, the underlying biological mechanisms of detected associations are largely unknown. METHODS: Sixty-four single-nucleotide polymorphisms (SNPs) in this cluster were analyzed for association with Fagerstrom Test for Nicotine Dependence score (FTND) and cigarettes per day (CPD) in male Chinese Han smokers (N = 2616). Next-generation bisulfite sequencing was used to discover smoking-associated differentially methylated regions (DMRs). Both cis-eQTL and cis-mQTL analyses were applied to assess the cis-regulatory effects of these risk SNPs. RESULTS: Association analysis revealed that rs4648317 was significantly associated with FTND and CPD (pâ =â .00018; pâ =â .00072). Moreover, 14 additional SNPs were marginally significantly associated with FTND or CPD (pâ =â .05-.01). Haplotype-based association analysis showed that one haplotype in DRD2, C-T-A-G, formed by rs4245148, rs4581480, rs4648317, and rs11214613, was significantly associated with CPD (pâ =â .0005) and marginally associated with FTND (pâ =â .003). Further, we identified four significant smoking-associated DMRs, three of which are located in the DRD2/ANKK1 region (pâ =â .0012-.00005). Finally, we found five significant CpG-SNP pairs (p = 7.9 × 10-9-6.6 × 10-6) formed by risk SNPs rs4648317, rs11604671, and rs2734849 and three methylation loci. CONCLUSIONS: We found two missense variants (rs11604671; rs2734849) and an intronic variant (rs4648317) with significant effects on ND and further explored their mechanisms of action through expression and methylation analysis. We found the majority of smoking-related DMRs are located in the ANKK1/DRD2 region, indicating a likely causative relation between non-synonymous SNPs and DMRs. IMPLICATIONS: This study shows that there exist significant association of variants and haplotypes in ANKK1/DRD2 region with ND in Chinese male smokers. Further, this study also shows that DNA methylation plays an important role in mediating such associations.
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Povo Asiático/genética , Biomarcadores/análise , Epigênese Genética , Polimorfismo de Nucleotídeo Único , Fumantes/psicologia , Fumar/genética , Tabagismo/genética , Adulto , Antígeno CD56/genética , Metilação de DNA , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas/genética , Receptores de Dopamina D2/genética , Fumar/epidemiologia , Tabagismo/epidemiologia , Tabagismo/psicologiaRESUMO
Background. The prevalence of e-cigarette use among youth is rising and may be associated with perceptions of health risks for these products. We examined how demographic factors and socioeconomic status (SES) are correlated with the perceived health risks of e-cigarette product contents among youth. Method. Data were from a national online survey of youth aged 13 to 18 between August and October 2017, weighted to be representative of the overall U.S. population in age, sex, race/ethnicity, and region. Survey analysis procedures were used. Results. Of 1,549 e-cigarette users and 1,451 never-e-cigarette users, 20.9% were Hispanic, 13.7% Black, 21.7% LGBTQ (lesbian/gay/bisexual/transgender/queer), and 49.3% in low-income families. With adjustment for e-cigarette use status, perceived health risks of nicotine and toxins/chemicals in e-cigarettes significantly differed by gender, race, sexual orientation, and SES (ps < .05). For example, adjusted odds of perceiving harm from nicotine were 60% higher in girls versus boys, 34% lower in non-Hispanic Blacks versus non-Hispanic Whites, 33% lower in urban versus suburban residents, 40% higher in LGBTQ versus straight-identifying individuals, and 28% lower in low-income versus high-income families. Lower parental education level also was associated with children's lower health risk perception of e-cigarette product contents. Conclusions. For youth, the perceived health risks of e-cigarette product contents were associated with demographics, sexual orientation, and SES. The findings may have relevance for developing communication and education strategies addressing specific youth audiences, especially those in vulnerable groups. These strategies could improve awareness among youth concerning the health risks of e-cigarettes, helping to prevent or reduce e-cigarette uptake and continued use.
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Grupos Minoritários/estatística & dados numéricos , Pobreza/estatística & dados numéricos , Produtos do Tabaco/economia , Vaping/epidemiologia , Adolescente , Fatores Etários , Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Masculino , Grupos Raciais/estatística & dados numéricos , Medição de Risco , Fatores Sexuais , Minorias Sexuais e de Gênero/estatística & dados numéricos , Fatores Socioeconômicos , Inquéritos e Questionários , Pessoas TransgêneroRESUMO
INTRODUCTION: Cigarette smoking is one of the largest causes of preventable death worldwide. This study aimed to identify susceptibility loci for age at smoking initiation (ASI) by performing an exome-wide association analysis. METHODS: A total of 2510 smokers of either African-American (AA) or European-American (EA) origin were genotyped and analyzed at both the single nucleotide polymorphism (SNP) and gene levels. After removal of those SNPs with a minor allele frequency (<0.01), 48091 and 34933 SNPs for AAs and EAs, respectively, were used to conduct a SNP-based association analysis. Gene-based analyses were then performed for all SNPs examined within each gene. Further, we estimated the proportion of variance explained by all common SNPs included in the analysis. RESULTS: The strongest signals were detected for SNPs rs17849904 in the pitrilysin metallopeptidase 1 gene (PITRM1) in the AA sample (p = 9.02 × 10-7) and rs34722354 in the discoidin domain of the receptor tyrosine kinase 2 gene (DDR2) in the EA sample (p = 9.74 × 10-7). Both SNPs remained significant after Bonferroni correction for the number of SNPs tested. Subsequently, the gene-based association analysis revealed a significantly associated gene, DHRS7, in the AA sample (p = 5.00 × 10-6), a gene previously implicated in nicotine metabolism. CONCLUSIONS: Our study revealed two susceptibility loci for age of smoking initiation in the two ethnic samples, with the first being PITRM1 for AA smokers and the second DDR2 for EA smokers. In addition, we found DHRS7 to be a plausible candidate for ASI in the AA sample from our gene-based association analysis. IMPLICATIONS: PITRM1 and DHRS7 for African-American smokers and DDR2 for European-American smokers are new candidate genes for smoking initiation. These genes represent new additions to smoking initiation, an important but less studied phenotype in nicotine dependence research.
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Negro ou Afro-Americano/genética , Marcadores Genéticos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fumar/genética , Tabagismo/genética , População Branca/genética , Adolescente , Adulto , Fatores Etários , Receptor com Domínio Discoidina 2/genética , Exoma/genética , Feminino , Frequência do Gene , Loci Gênicos , Genótipo , Humanos , Masculino , Metaloendopeptidases/genética , Oxirredutases/genética , Fenótipo , Prevalência , Fumar/epidemiologia , Estados Unidos/epidemiologia , Sequenciamento do Exoma , Adulto JovemRESUMO
We report herein the preparation of two families of secondary amines by the reactions of two equivalents of monoamines with either 2,4 or 2,6-difluoronitrobenzenes in N,N-dimethylacetamide in the presence of anhydrous potassium carbonate, as precursors of biologically important nitric oxide donating N-nitrosamines. In both instances, these compounds could be prepared in quantitative yield when the reaction temperature was held below 130°C. Above this reaction temperature, an unexpected cyclization reaction between the nitro and newly formed adjacent secondary amine group leads to the formation of benzimidazole or quinoxaline rings in low yields. Reasonable reaction mechanisms for the cyclization reaction are proposed.
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The direct physiological effects that promote nicotine dependence (ND) are mediated by nicotinic acetylcholine receptors (nAChRs). In line with the genetic and pharmacological basis of addiction, many previous studies have revealed significant associations between variants in the nAChR subunit genes and various measures of ND in different ethnic samples. In this study, we first examined the association of variants in nAChR subunits α2 (CHRNA2) and α6 (CHRNA6) genes on chromosome 8 with ND using a family sample consisting of 1,730 European Americans (EAs) from 495 families and 1,892 African Americans (AAs) from 424 families (defined as the discovery family sample). ND was assessed by two standard quantitative measures: smoking quantity (SQ) and the Fagerström Test for ND (FTND). We found nominal associations for all seven tested SNPs of the genes with at least one ND measure in the EA sample and for two SNPs in CHRNA2 in the AA sample. Of these, associations of SNPs rs3735757 with FTND (P = 0.0068) and rs2472553 with both ND measures (with a P value of 0.0043 and 0.00086 for SQ and FTND, respectively) continued to be significant in the EA sample even after correction for multiple tests. Further, we found several haplotypes that were significantly associated with ND in the EA sample in CHRNA6 and in the both EA and AA samples in CHRNA2. To confirm the associations of the two genes with ND, we conducted a replication study with an independent case-control sample from the SAGE study, which showed a significant association of the two genes with ND, although the significantly associated SNPs were not always the same in the two samples. Together, these findings indicate that both CHRNA2 and CHRNA6 play a significant role in the etiology of ND in AA and EA smokers. Further replication in additional independent samples is warranted.
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População Negra/genética , Receptores Nicotínicos/genética , Tabagismo/genética , População Branca/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 8 , Haplótipos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.
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Cromossomos Humanos Par 15 , Variação Genética , Fumar/efeitos adversos , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , População Negra , Feminino , Frequência do Gene , Genética Populacional , Humanos , Pneumopatias/etiologia , Pneumopatias/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Risco , População BrancaRESUMO
On the basis of the converging evidence showing regulation of drinking behavior by 5-HT3AB receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally significantly associated with AD with odds ratio (OR) and 95 % confidence interval of 0.212 and 0.073, 0.616 (P = 0.004) and 0.261 and 0.088, 0.777 (P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P < 1 × 10(-6) for prediction accuracy of the two models based on 10(6) permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD (P < 0.001) in carriers of genotype combinations 5'-HTTLPR:LL/LS(SLC6A4)-rs1042173:TT/TG(SLC6A4)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B) and 5'-HTTLPR:LL/LS(SLC6A4)-rs10160548:GT/TT(HTR3A)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B). Combining all five genotypes resulted in an OR of 3.095 (P = 2.0 × 10(-4)) for AD. Inspired by these findings, we conducted the analysis in an independent sample, OZ-ALC-GWAS (N = 6699), obtained from the NIH dbGAP database, which confirmed the findings, not only for all three risk genotype combinations (Z = 4.384, P = 1.0 × 10(-5); Z = 3.155, P = 1.6 × 10(-3); and Z = 3.389, P = 7.0 × 10(-4), respectively), but also protective effects for rs33940208:T (χ (2) = 3.316, P = 0.0686) and rs2276305:A (χ (2) = 7.224, P = 0.007). These findings reveal significant interactive effects among variants in SLC6A4-HTR3A-HTR3B affecting AD. Further studies are needed to confirm these findings and characterize the molecular mechanisms underlying these effects.
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Alcoolismo/genética , Receptores 5-HT3 de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Razão de Chances , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Risco , População Branca/genética , Adulto JovemRESUMO
Atherosclerosis, a leading cause of death worldwide, is associated with the excessive proliferation of vascular smooth muscle cells. Nitrogen monoxide, more commonly known as nitric oxide, inhibits this uncontrolled proliferation. Herein we report the preparation of two families of nitric oxide donors; beginning with the syntheses of secondary amine precursors, obtained through the reaction between 2 equiv of various monoamines with 2,4 or 2,6-difluoronitrobenzene. The purified secondary amines were nitrosated then subjected to a Griess reagent test to examine the slow and sustained nitric oxide release rate for each compound in both the absence and presence of reduced glutathione. The release rate profiles of these two isomeric families of NO-donors were strongly dependent on the number of side chain methylene units and the relative orientations of the nitro groups with respect to the N-nitroso moieties. The nitrosated compounds were then added to human aortic smooth muscle cell cultures, individually and in tandem with S-2-amino-6-boronic acid (ABH), a potent arginase inhibitor. Cell viability studies indicated a lack of toxicity of the amine precursors, in addition to anti-proliferative effects exhibited by the nitrosated compounds, which were enhanced in the presence of ABH.
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Aminas/química , Arginase/antagonistas & inibidores , Inibidores Enzimáticos/química , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Arginase/metabolismo , Ácidos Borônicos/química , Ácidos Borônicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Inibidores Enzimáticos/toxicidade , Humanos , Isomerismo , Músculo Liso Vascular/citologia , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/toxicidade , NitrosaçãoRESUMO
INTRODUCTION: Cigarette smokers experience higher levels of depressive symptoms and are more likely to be diagnosed with depressive disorders than nonsmokers. To date, the nature of the smoking-depression relationship has not been adequately studied among heavy smokers, a group at elevated risk for poor health outcomes. In this study, we examined depressive symptom expression among heavy smokers while considering the moderating roles of smoking status, gender, and race. We also explored whether amount of tobacco usually consumed had an impact. METHODS: We extracted data from a large, highly nicotine-dependent, nontreatment cigarette smoking study sample (N = 6,158). Participants who consented were screened for major exclusions, and they completed questionnaires. RESULTS: Smokers reported a higher, clinically meaningful level of depressive symptoms relative to nonsmokers (27.3% of smokers vs. 12.5% of nonsmokers) scored above the clinical cutoff on the Center for Epidemiological Studies Depression (CES-D) scale (p < .001), which differed among race × gender subgroups. Further, amount of daily intake was inversely associated with self-report of depressive symptoms. For every 10-cigarette increment, the likelihood of scoring above the CES-D clinical cutoff decreased by 62% (p < .0001). CONCLUSIONS: These findings improve our understanding of tobacco's influence on depressive symptom expression among heavy smokers, with implications for tailoring evidence-based tobacco treatments.
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Depressão/epidemiologia , Depressão/etiologia , Fumar/epidemiologia , Fumar/psicologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.
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Cromossomos Humanos Par 15/genética , Neoplasias Pulmonares/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Receptores Nicotínicos/genética , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. METHODS: 76 healthy adults aged 18-64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 µg, N = 32), mRNA vaccine (10, 20, or 50 µg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. CLINICALTRIALS: govNCT05272605. FINDINGS: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. INTERPRETATION: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. FUNDING: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.
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Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Austrália , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas de mRNA , SARS-CoV-2 , Adolescente , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
Diseases related to smoking are the second leading cause of death in the world. Cigarette smoking is a risk factor for several diseases such as cancer and cardiovascular and respiratory disorders. Despite increasing evidence of genetic determination, the susceptibility genes and loci underlying various aspects of smoking behavior are largely unknown. Moreover, almost all reported genome-wide association studies (GWASs) have been performed on samples of European origin, limiting the applicability of the results to other ethnic populations. In this first GWAS on smoking behavior in an Asian population, after analyzing 8,842 DNA samples from the Korea Association Resource project with 352,228 single nucleotide polymorphisms (SNPs) genotyped for each sample, we identified 8 SNPs significantly associated with smoking initiation (SI) and 4 with nicotine dependence (ND). Because of the current unavailability of an independent Asian smoking sample, we replicated the discoveries in independent samples of European-American and African-American origin. Of the 12 SNPs examined in the replicated samples, we identified two SNPs, in the regulator of G-protein signaling 17 gene (rs7747583, p value(meta) = 6.40 × 10(-6); rs2349433, p value(meta) = 5.57 × 10(-6)), associated with SI. Also, we found two SNPs significantly associated with ND; one in the FERM domain containing 4A (rs4424567, p value(meta) = 2.30 × 10(-6)) and the other at 7q31.1 (rs848353, p value(meta) = 9.16 × 10(-8)). These SNPs represent novel targets for examination of smoking behavior and warrant further investigation using independent samples.
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Povo Asiático/genética , Cromossomos Humanos Par 7/genética , Proteínas RGS/genética , Fumar/epidemiologia , Fumar/genética , Tabagismo/epidemiologia , Tabagismo/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , República da Coreia/epidemiologiaRESUMO
Background Although tobacco product use and transitions have been characterized in the general population, few studies have focused on individuals with established cardiovascular disease (CVD) in a population-based sample. Methods and Results We examined tobacco use prevalence and longitudinal patterns of tobacco product transitions in adults (≥18 years) of the nationally representative PATH (Population Assessment of Tobacco and Health) study, from 2013 to 2014 (Wave 1) through 2016 to 2018 (Wave 4). Prevalent CVD was classified through self-report of having had a heart attack, heart failure, stroke, or other heart condition. Factors associated with tobacco product use and transitions were investigated using survey logistic regression. We examined 2615 participants with self-reported CVD at Wave 1. Overall, 28.9% reported current tobacco use, equating to ≈6.2 million adults in the United States with prevalent CVD and current tobacco use. Among adults with CVD who are current tobacco users, the most commonly used product was cigarettes (82.8%), followed by any type of cigar (23.7%), and e-cigarette use (23.3%). E-cigarette use without concurrent cigarette use among participants with prevalent CVD was uncommon (1.1%). Factors associated with tobacco use were younger age, male sex, had lower education level, and lack of knowledge about the association between smoking and CVD. Men with prevalent CVD were less likely to use e-cigarettes compared with women (odds ratio [OR], 0.7; 95% CI, 0.5-0.9). Among cigarette users with CVD, transition rates between Waves 1 and 4 demonstrated <5% decrease in cigarette, with a 0.5% increase in e-cigarette use. Only ≈10% were in formal tobacco cessation programs. Conclusions Despite known harmful cardiovascular effects, over one fourth of adults with prevalent CVD use tobacco products and few quit smoking over the 4 waves of the PATH data set.
Assuntos
Doenças Cardiovasculares/epidemiologia , Sistemas Eletrônicos de Liberação de Nicotina , Fumantes , Abandono do Hábito de Fumar , Fumar/efeitos adversos , Produtos do Tabaco/efeitos adversos , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Fatores de Risco , Fumar/epidemiologia , Fatores de Tempo , Estados Unidos/epidemiologia , Vaping/efeitos adversos , Vaping/epidemiologia , Adulto JovemRESUMO
Studies reporting clinical symptoms related to electronic nicotine delivery systems (ENDS) usage, especially types of devices and e-liquids, are sparse. The sample included 1,432 current ENDS users, ages 18-64, from a nationwide online survey conducted in 2016. ENDS use included device types, nicotine content, flavors, and e-liquid used. Outcomes included any e-cigarette, or vaping, product use-associated lung injury (EVALI)-like symptoms (e.g., cough, shortness of breath, nausea) as well as any clinical symptoms. Of the sample, 50% were female, 23% non-Hispanic (NH) White, 23% NH Black, 54% Hispanic, 18% aged 18-24, 17% LGBTQ, 41% with <$50 K income, 55% 1 + any symptoms, and 33% 1 + any EVALI-like symptoms. Cough and nausea were most prevalent among EVALI-like symptoms (27% and 7.3%, respectively). The proportion having any EVALI-like symptoms was higher in the following groups: younger, Hispanic, current smokers, and current other product users. With multiple adjustments, participants who used refillable devices, varied nicotine content, used flavored products, or made their own e-liquids were more likely to have clinical symptoms than their counterparts. For example, the odds (95% CI) of having 1 + EVALI-like symptoms in participants who used refillable devices with e-liquid pour or e-liquid cartridge replacement were 1.70 (1.13, 2.56) and 1.95 (1.27, 2.99), respectively, compared to the non-refillable group. Use of products (devices and e-liquids) that can be altered and flavored products are associated with higher odds of having clinical symptoms, including EVALI-like symptoms.
RESUMO
Vaping is popular among adolescents. Previous research has explored sources of information and influence on youth vaping, including marketing, ads, family, peers, social media, and the internet. This research endeavors to expand understanding of peer influence. Our hypothesis is that friends' influence on teen vapers' first electronic nicotine delivery systems (ENDS) use varies by demographic variables and awareness of ENDS advertising. In August-October 2017, youth (n = 3174) aged 13-18 completed an online survey to quantify ENDS behaviors and attitudes and were invited to participate in follow-up online research in November-December 2017 to probe qualitative context around perceptions and motivations (n = 76). This analysis focused on the ENDS users, defined as having ever tried any ENDS product, from the survey (n = 1549) and the follow-up research (n = 39). Among survey respondents, friends were the most common source of vapers' first ENDS product (60%). Most survey respondents tried their first ENDS product while "hanging out with friends" (54%). Among follow-up research participants, the theme of socializing was also prominent. ENDS advertising and marketing through social media had a strong association with friend networks; in fact, the odds of friends as source of the first vaping experience were 2 times higher for those who had seen ENDS ads on social media compared with other types of media. The influence of friends is particularly evident among non-Hispanic Whites, Hispanics/Latinos, those living in urban areas, those living in high-income households, those with higher self-esteem, and those who experiment with vaping. These findings support the premise that peer influence is a primary social influencer and reinforcer for vaping. Being included in a popular activity appears to be a strong driving force.